The long term goal of this project is to understand the function of costimulatory pathways in regulating anti-microbial T cell immunity. To achieve this goal, two established models of infection, Leishmania major (L. major) and Lymphocytic choriomeningitis virus (LCMV), will be used to dissect functions of newly discovered T cell costimulatory pathways individually and analyze interactions with well-characterized pathways in regulating anti-microbial immune responses. The L. major model will enable us to dissect the roles of T cell costimulatory pathways in regulating CD4 T helper commitment to a Thl/Th2 response, and CD4 and CD8 memory responses during this well characterized parasitic infection. The LCMV model enables us to investigate the roles of T cell costimulatory pathways in regulating CD8 T cell activation, differentiation, effector and memory responses during acute viral infection and in regulating "exhausted" CD8 T cells during chronic viral infection. Our specific aims are: 1. To investigate the roles of the PD-I:PD-LI/PD-L2 and CTLA-4 costimulatory pathways in regulating the pathogenesis of L. Major. We will compare the roles of PD-I:PD-L1/PD-L2 pathway during the induction, differentiation, and effector responses to L. major and to study its interactions with the B7:CTLA-4 costimulatory pathway, and the interplay between the PD-1 and CTLA-4 pathways during the development of immunity to L. major. 2. To analyze the roles of the PD-I:PD-L1/PD-L2 and CTLA-4 costimulatory pathways in regulating the function of LCMV-specifie CD8 T cells. We will examine whether signals from PD-L1 or PD-L2 or both are involved in inhibiting the function of these exhausted CD8 T cells in chronic LCMV infection, and investigate the role of the PD-1 pathway and its interaction with the CTLA-4 pathway in regulating virus specific T cell responses during both acute and chronic LCMV infection. 3: To dissect the roles of novel and characterized costimulatory pathways in T cell differentiation, effector, and memory responses to infection with L. major and LCMV. As novel reagents (mAbs, Ig fusion proteins, transgenic / knockout mouse strains) to dissect new and well characterized T cell costimulatory pathways become available, we will build on the studies in Aims 1 and 2 to further investigator how T cell costimulatory pathways regulate the outcome of infections with L. major and LCMV. Taken together, studies in aims 1-3 should provide insight into the role of costimulatory pathways in regulating anti-microbial CD4 and CD8 T cell responses and may reveal how manipulation of costimulatory pathways can enhance anti-microbial immunity.